Intercellular – indirect – communication
•transmission of chemical signals: sending cell – signal – transmitting
medium – receiving cell
tissue hormone
hormone
blood
intercellular fluid
neurocrine
neurotransmitter
synaptic cleft
Intercellular – indirect – communication
• signal: also membrane-bound, not only secreted (juxtacrine action)
adhesion receptors
Intercellular – indirect – connections
• signal: can be membrane-bound, not only secreted (juxtacrine action)
adhesion receptors
Integrins
• a, b heterodimers
• 18 a, 8 b subunits, but „only" in
~24 combinations
• Ca2+ is needed for the
stabilisation of the domain
structure
RGD: Arg-Gly-Asp
Integrins
Integrins
Integrins
Integrins
• C-term.: anchored to the cytoskeleton (actin, IF [a6b4] )
• initiate diverse signal transduction pathways
• extracellular conformational
change: ON / OFF state
(see later...)
Immunoglobulin superfamily (IgSF [CAMs])
• 70-120 aa Ig domains, Ca-independent adhesion
• heterophilic connections to other adhesion receptors
• homophilic binding is also possible
Immunoglobulin superfamily (IgSF [CAMs])
• cis andtrans „zippers” – strong adhesice force between cells
Selectins
• 1960’s : limfocyte homing
• transmembrane glycoproteins, spec. oligosaccharide binding sites
(CD26L, LECAM-1, LAM-1)
(lectins)
E: endothelial cell
P: platelet and endothelial cell
L: leukocyte
(CD26E, LECAM-2, ELAM-1)
(CD26P, LECAM-3
• Ca-dependent binding
• malfunctioning: allergy, psoriasis, MS,
rheumathoid arthritis, graft vs host
disease + malignacy
Cadherins
• Ca-dependent adhesion, homophilic
connections: sorting out different cellular
clusters; ~ 130 KDa
• classical, desmosomal and protocadherin
subgroups (>350 types!)
Cadherins
• homophilic connections
(desmosomal cadherins can form
heterophilic connections, as well)
• classical: actin cytoskeleton;
desmosomal: IF (Keratin)
• protocadherins (PCDHs): nonclustered / clustered / lipid or
7TM – mainly within the CNS
Cadherins
• classical signaling: Wnt/b-catenin or small GTPases
Cadherins
special adhesion receptors: Notch / Delta
• lateral inhibition: selection of differentiating cells from a uniform
layer of non-committed cells
differentiating cell
non-committed cell
special adhesion receptors: Notch / Delta
special adhesion receptors: Notch / Delta
special adhesion receptors: Notch / Delta
• multiple proteolysis:
4 cleavage sites
• Notch intracellular
fragment (Nicd):
transcription factor
-> regulation of gene
expression upon cellto-cell interactions
ligand interaction
cleavage
special adhesion receptors: Notch / Delta
special adhesion receptors: Notch / Delta
Importance of adhesion molecules in
health and disease
Hemostasis
• "inside-out" signaling: changes in
integrin affinity due to a
confomational change (a2b3 integrin)
- damage -> a2b1 collagen receptor
binding -> ADP release, thrombin ->
a2b3 activation -> fibrinogen binding
-> fibrin formation, coagulation
Hemostasis
• initiation – extension - stabilisation
- initiation by collagen –
platelet interactions
(outside-in integrin
signaling)
- platelet activation by G protein
coupled receptors (inside-out
integrin signaling)
Hemostasis
NCAM / L1 and axonal elongation / pathfinding
• NCAM, L1: neuron-specific IgSF members
• frequent coreceptors: integrins, growth
factors
• L1: semaphorin3A coreceptor; growth cone
collapse, repellent signal
• PSA-NCAM: embryonic form
(polisyalic acid) – faster
neurite extension
• NCAM: adult form;
stabilisation of axons
NCAM / L1 and axonal elongation / pathfinding
Endothelial intercellular conncetions
• adhesion complexes:
- tight junction
- adherens junction
- gap junctions
- dezmosomes /
hemidesmosomes
Focal adhesion (integrins)
• cell/ECM connection: "outside-in" signaling
• adhesion-dependent proliferation,
migration or diapedesis (leukocyte
infiltration)
• abnormal signaling: malignant
transformation
• RGD motif: ECM components
(proteoglycan, fibronectin, laminin,
etc)
Hemidesmosomes
• epithelium / MB ECM
connections: "outside-in"
integrin signaling
• connections to the basal
lamina (laminin): keratin
filaments
• epidermolysis bullosa: abnormal
hemidesmosome structure (a6 / b4
integrin, collagenVII, laminin-5 – aberrant
or loss-of-function variants)
Hemidesmosomes
• bullous pemphigoid
(desmoglein auto-antobodies / mutations/
ectoproteases / aberrant endocytosis) :
problems with desmosomal
cadherin functions
Endothelium and leukocyte infiltration
recording by Csépányi-Kömi Roland
Semmelweis Medical University, Inst. Physiology, Budapest; Ludwig-Maximilians Universität, Walter Brendel Center of Experimental Medicine, München
Endothelium and leukocyte infiltration
recording by Csépányi-Kömi Roland
Semmelweis Medical University, Inst. Physiology, Budapest; Ludwig-Maximilians Universität, Walter Brendel Center of Experimental Medicine, München
Endothelium and leukocyte infiltration
Endothelium and leukocyte infiltration
Endothelium and leukocyte infiltration
• LAD (leukocyte adhesion deficiency): lack of b2 integrin ->
no leukocyte adhesion and lack of infiltration -> sever
bacterial infections
Leukocyte adhesion / homing
• over-activation:
inflammation, auto-immune
diseases
• therapy?
- anti-selectin antibody
- blocking of selectins:
excess ligand
- selectin antagonists
Leukocyte adhesion / homing
Endothelium and leukocyte infiltration
• VE-cadherin: hexamer,
strong adhesive force
• binds to vimentin and actin
1st step: endothelial adhesion connections weaken
• VE-cadherin
endocytosis
• disconnection
from the
cytoskeleton
Endothelium and leukocyte infiltration
2nd step: diapedesis (infiltration)
• paracellular / junctional
transmigration
• transcellular transmigration
Endothelium and leukocyte infiltration
• premigratory stage
• beginning of transmigration
• during transmigration
Endothelium and leukocyte infiltration
• end of transmigration
Endothelium and leukocyte infiltration
Epithelial-mezenchimal transition (EMT)
• changes in adhesive properties -> differentiation, sorting of
different cell types, developmental cell migration
• neural crest:
1. induction
2. delamination
3. migration
4. differentiation
• E and N-cadherin, NCAM
decrease, cadherin 7 and 11
expr. increase
Epithelial-mezenchimal transition (EMT) and metastasis
• normal, polarized epithelial cells
Epithelial-mezenchimal transition (EMT) and metastasis
• initial steps of intravasation
E-cadherin , MMP 
collagen, integrin signaling, N-cadherin 
E-cadherin functions 
membrane ruffling 
Epithelial-mezenchimal transition (EMT) and metastasis
• initial steps of intravasation
Epithelial-mezenchimal transition (EMT) and metastasis
• final steps of intravasation
- lamellopodium/filopodium: horizontal
migration over the MB
- invadopodia: ventral
migration across the MB
• adhesive ring +
enhanced ECM
degradation
Epithelial-mezenchimal transition (EMT) and metastasis
• final steps of intravasation